The overall goal of this application is to continue the efforts of the Type 1 Diabetes Mouse Resource (T1DR) originally established by NIDDK at The Jackson Laboratory (Jackson) in 2001. To date the mission of the T1DR has been to import, curate, perform genotypic and phenotypic validation, cryopreserve, and distribute extant mouse stocks identified as important to T1D research. Specific aim 1 of this renewal application is to continue such efforts. However, it is also our goal to expand the efforts of the T1DR in several ways. One such area of expansion will focus on humanized mouse stocks for T1D research. These include a series of NOD background mice homozygous for either the scid or rag1null mutations eliminating endogenous lymphocytes combined with an inactivated variant of the gene encoding the common gamma chain component of the IL2, IL4, IL7, IL15, and IL21 receptors resulting in the ablation of NK cells, and preventing life-shortening lymphoid tumorigenesis. The combined effects of such genetic manipulations allow these strains (respectively designated NSG and NRG) to support high levels of engraftment with human immune cells, pancreatic islets, and other tissues. The utility of such NSG and NRG strains has been continually broadened by the introduction of additional human genetic components, such as various HLA class I and II alleles associated in epidemiological studies with susceptibility or resistance to T1D and other autoimmune diseases. Immuno- competent NOD mice carrying disease associated HLA genes have also proven useful in identifying autoreactive T cell populations relevant to T1D development in humans. Continued genomic refinements of NOD, NSG, and NRG mice are required to optimize humanization of their immune systems, not only to screen for the presence of diabetogenic effector T cells, but also to develop potentially clinically relevant disease intervention approaches. Thus, specific aim 2 is for the T1DR to pursue a new goal of producing and/or perfecting, based on the recommendations of the external user community, additional T1D relevant mouse stocks with a focus on those that allow testing in vivo of human tissues and cells, including analyses of autoimmune responses of relevance to T1D patients. In order to effectively utilize the ever expanding array of NOD, NSG, and NRG background stocks that can be employed to address various facets of human T1D pathogenesis, the external research community will need to be better informed of their availability, uses, and limitations. To achieve this goal, specific aim 3 is to provide, through boh webinars and onsite conferences at Jackson, avenues enabling the research community to become better informed on the availability, uses, and limitations of mouse models that can be employed to study various pathological components of T1D development in humans. ! PUBLIC HEALTH RELEVANCE: Type 1 diabetes (T1D) is a life threatening disease that results when interactions between a large number of genes results in the generation of T lymphocytes which mediate the aberrant autoimmune destruction of insulin producing cells within the pancreas. Much of what has been learned about the pathogenic basis of T1D has come from the analyses of an ever-widening array of disease relevant mouse models. These include mouse models in which T1D relevant autoimmune responses are mediated by genetically encoded molecules and/or transplanted cells of human origin. For logistical and expense reasons, it is difficult for most investigators to continually maintain the full array of mouse models that could possibly be used to address various questions about the basis of T1D, and/or supply such stocks to other researchers. Thus, the goal of this proposal is to continue operations at The Jackson Laboratory (Jackson) of the type 1 diabetes mouse resource (T1DR). The mission of the T1DR is to import, re-derive to a high-level health status, curate, genotypically and phenotypically validate, cryopreserve, and distribute mouse stocks of value to the T1D research community.